A new hydroxydiphosphine as a ligand for Rh(I)-catalyzed enantioselective hydrogenation

Article abstract of DOI:10.1016/S0957-4166(02)00372-5

A new diphosphine ligand bearing a hydroxy group in the backbone was synthesized starting from 9-bromocamphor. The rhodium(I) complex based on this ligand was tested in the hydrogenation of α- and β-amino acid precursors. The activity and selectivity of the catalyst were found to be strongly dependent upon the nature of the substrate. Thus, β-acetylamino carboxylates were obtained with up to 97% ee.

Full text of DOI:10.1016/S0957-4166(02)00372-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1615–1620
A new hydroxydiphosphine as a ligand for Rh(I)-catalyzed
enantioselective hydrogenation
Igor V. Komarov,a,* Axel Monsees,b Renat Kadyrov,b Christine Fischer,a Ute Schmidta and
Armin Bo¨rnera,c,
*
aInstitut fu¨r Organische Katalyseforschung an der Universita¨t Rostock e.V., Buchbinderstraße 5/6, D-18055 Rostock, Germany
bDegussa AG, Projekthaus Katalyse, Gescha¨ftsbereich Creavis, Industriepark Hoechst, Geba¨ude G 830,
D-65926 Frankfurt/Main, Germany
cFachbereich Chemie der Universita¨t Rostock, A. Einstein Straße 3a, D-18059 Rostock, Germany
Received 23 May 2002; accepted 9 July 2002
Abstract—A new diphosphine ligand bearing a hydroxy group in the backbone was synthesized starting from 9-bromocamphor.
The rhodium(I) complex based on this ligand was tested in the hydrogenation of a- and b-amino acid precursors. The activity and
selectivity of the catalyst were found to be strongly dependent upon the nature of the substrate. Thus, b-acetylamino carboxylates
were obtained with up to 97% ee. © 2002 Published by Elsevier Science Ltd.
1. Introduction
conversion of camphor to a variety of related bromo-
substituted derivatives, originally developed by
Money,5 make this natural terpenoid attractive for the
synthesis of functionalized diphosphines.6 One of the
most easily available bromosubstituted camphor deriva-
tives, apart from the commercially available 3-bromo-
camphor 2, is 9-bromocamphor 4 which can be derived
from camphor by a simple three-step protocol via bro-
mides 2 and 3 on large scale (Scheme 1).5,7
We have focused our research on the synthesis and
application of chiral hydroxydiphosphine ligands in the
rhodium(I)-catalyzed enantioselective hydrogenation
for several years.1 In these studies, we and other
researchers have provided several pieces of evidence
that the hydroxy group can actively participate in the
catalytic process.2 Thus, the additional functional
group may significantly affect the activity and selectiv-
ity of these catalysts, even in cases where the hydroxy
group was found to be remote from the metal in the
relevant precatalysts.3 This and other observations gave
proof that the hydroxy group if appropriately placed in
the catalyst can change the electronic and steric proper-
ties of the metal center and the substrate, well-known in
enzyme catalysis as ‘induced fit’.4
Subsequent oxidation of 4, first using SeO2 to form the
‘quinone’ 5, followed by H2O2 gave the anhydride 6 in
high yield. The latter was reduced with LiAlH4 to give
diol 8. Compound 8 was also obtained from 4 using a
Baeyer–Villiger
rearrangement–LiAlH4
reduction
sequence. The rearrangement proceeded in the presence
of the p-toluenesulfonic acid with the preferential for-
mation of the desired lactone 7.
Herein, we describe a new hydroxy-substituted diphos-
phine and its performance in the enantioselective
hydrogenation of functionalized olefins of pharmaceuti-
cal relevance. Our approach for the synthesis of the
ligand takes advantage of the availability of the ‘chiral
pool’ material (R)-camphor 1. Simple protocols for the
We analyzed the enantiomeric purity of diol 8 by
HPLC on a chiral stationary phase. It was found to be
enantiomerically pure within experimental errors of the
technique (>98% ee). In parallel, the enantiomer, (R)-8,
was prepared starting from (S)-camphor. Surprisingly,
the enantiomeric purity of (R)-8 was also >98% ee,
though the starting material, (S)-camphor, is known to
be of relatively low enantiomeric purity (78.6–92.8%
ee).8 Obviously, this is the result of several recrystalliza-
tions of the intermediates throughout the synthesis.
* Corresponding authors. Fax: Int.+49-(0)381-4669324; e-mail:
ik214@mail.yahoo.com; armin.boerner@ifok.uni-rostock.de
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00372-5

1616
I. V. Komaro6 et al. / Tetrahedron: Asymmetry 13 (2002) 1615–1620
Scheme 1.
The diol 8 was selectively esterified at the less hindered
OH group with TsCl to give the tosylate 9. Subse-
quently, the remaining hydroxy group in 9 was pro-
tected as the THP–acetal 10. Protection of the
HO-group was necessary to avoid undesired cyclization
of 9 that readily proceeds under basic conditions to
yield the bicyclic ether 11. Nucleophilic substitution of
the tosylate group in 10 by Ph2PLi followed by depro-
tection gave the target hydroxydiphosphine 12. This
ligand can form a seven-membered chelate ring upon
coordination with a transition metal. It possesses no
symmetry elements (C1-symmetry group) and a hydroxy
group on a conformationally flexible arm remote from
the diphenylphosphine moiety.
of their trans-relationship to the p-accepting phospho-
rus atoms. These NMR data allowed us to exclude
structures with the OH group coordinated to the metal
center, as this coordination would lead to significant
changes in the 31P and 13C NMR spectra of the lig-
and.10 Molecular modelling of the complex showed that
such coordination is prevented by the 2-CH3 group
which acts as a barrier, meaning that coordination of
the OH group to the metal center would lead to signifi-
cant steric congestion.
3. Enantioselective hydrogenation
The complex [Rh(12)(COD)]BF4 was used as a precata-
lyst in the hydrogenation of different prochiral sub-
strates. The results are listed in the Table 1. As clearly
to be seen activity and enantioselectivity of the catalyst
are highly dependent on the nature of the substrate.
The enantioselectivities range from 9% ee for the ‘stan-
dard’ substrate itaconic acid 16 to 97% ee for (E)-
methyl-3-acetylaminocrotonate 17.11 The high activity
observed in the hydrogenation of standard substrates
indicates that, in accordance with the conclusion
derived from the analysis of the 31P NMR spectrum of
the precatalyst, there is no interaction between the
hydroxy group and the metal in catalytically relevant
intermediates.10 The new catalyst is also suitable for the
hydrogenation of b-amino acid precursors 17–20. In the
hydrogenation of the latter, the enantioselectivity for
the (E)-isomers was good, but is only moderate for the
(Z)-isomers.
2. Synthesis and characterization of the precatalyst
The precatalyst [Rh(12)(COD)]BF4 was synthesized by
reaction of [Rh(COD)acac] with diphosphine 12 in
THF and subsequent addition of HBF4. The complex
was precipitated from the mixture as a yellow powder
by the addition of ether. Due to the presence of residual
THF and ether the complex had no satisfactory micro-
analytical data, but was fully characterized by its spec-
troscopic data. The 31P NMR spectrum contained two
double doublets at l 22.3 and 16.7 (JPP=41.6, JPꢀRh
144.3 Hz). Such chemical shifts and coupling constants
are characteristic of Rh(I) complexes bearing diphos-
phine ligands with C1-symmetry.9 In the 13C NMR
spectrum, the methine carbons of the COD ligands
gave resonances between l 96–106, which is indicative

I. V. Komaro6 et al. / Tetrahedron: Asymmetry 13 (2002) 1615–1620
1617
a
Table 1. Hydrogenation results of prochiral substrates 13–22 with Rh[(12)(COD)]BF4
Substrate
R2
Solvent
Time
Con. (%)
ee (%)
No.
13
R1
R3
H
R4
COOMe
COOH
NHAc
NHAc
COOMe
COOH
H
Ph
MeOH
CH2Cl2
MeOH
CH2Cl2
MeOH
CH2Cl2
MeOH
CH2Cl2
MeOH
CH2Cl2
Toluene
MeOH
CH2Cl2
toluene
MeOH
CH2Cl2
MeOH
CH2Cl2
1.5 min
5 min
1.5 min
8 min
100
100
100
100
100
100
100
62
100
100
98
100
72
11 (S)
24 (S)
57 (S)
49 (S)
70 (S)
75 (S)
9 (S)
10 (S)
93 (R)
95 (R)
97 (R)
46 (R)
58 (R)
50 (R)
81 (R)
82 (R)
54 (R)
12 (R)
14
H
Ph
15
CH2COOMe
CH2COOH
COOMe
H
H
6 min
3.5 min
1.5 min
300 min
40 min
12 min
300 min
20 min
45 min
700 min
120 min
\24 h
13 h
16
H
H
17
CH3
NHAc
18
COOMe
H
NHAc
CH3
7
82
54
53
19
20
COOH
COOH
H
H
CH3
NHAc
CH3
NHAc
\24 h
8
a Conditions for the hydrogenation: molar catalyst–substrate ratio 1:100, 1 bar H2, 25°C.
In general, the difference in enantioselectivity observed
in the hydrogenation of carboxylic acids and their
corresponding esters is notable. For example, itaconic
acid 16 was reduced with poor enantioselectivity
whereas its methyl ester 15 was obtained with good ee,
irrespective of the solvent used. In contrast, the hydro-
genation of (Z)-2-acetamidocinnamic acid 14 was supe-
rior than the reaction with its methyl ester 13 as
substrate. A clear dependence of the enantioselectivity
and the rates of the hydrogenation on the solvent
polarity was noted. In most cases the enantioselectivi-
ties were higher in solvents with low polarity (CH2Cl2,
toluene), than in methanol. The rate followed an oppo-
site tendency.
Ar atmosphere by using standard Schlenk techniques.
Thin-layer chromatography was performed on pre-
coated TLC plates (silica gel 60 F254, Merck). Flash
chromatography was carried out with silica gel 60
(particle size 0.040–0.063 mm, Merck). Melting points
are not corrected. NMR spectra were recorded at the
following frequencies: 400.13 MHz (1H), 100.63 MHz
1
(13C), 161.98 MHz (31P). Chemical shifts of H and 13C
NMR spectra are reported in ppm downfield from
TMS as internal standard. Chemical shifts of 31P NMR
spectra are referred to H3PO4 as external standard.
Elemental analyses were performed with a LEGO
CHNS-932.
Hydrogenation experiments were carried out under nor-
mal pressure and isobaric conditions with an automati-
cally registering gas measuring device (1.0 atm overall
pressure over the solution). The experiments were per-
formed in 15.0 mL of solvent at 25.0°C. The conversion
of the dehydroamino acids as well as the enantioselec-
tivity of the products were determined by GC. The
acids were esterified with trimethylsilyldiazomethane
before the GC-measurements: FID, Carrier gas: Ar: 1
mL/min; methyl N-acetylphenylalaninate: fused silica,
In summary, a new chiral hydroxyphosphine has been
synthesised starting from (R)-camphor. Its utility as a
ligand in the Rh(I)-catalysed asymmetric hydrogenation
of a- and b-acetyl dehydroamino acids has been
demonstrated. Remarkable differences were noted when
carboxylic acids or their esters were used as substrates.
Work is now in progress in order to elucidate the
reasons for this observation.
10 m, XE-60-L-valin-tert-butylamide, ID 0.2 mm; oven
4. Experimental
4.1. General
temperature: 150°C; dimethyl methylsuccinate: fused
silica, Lipodex E (Machery and Nagel), 25 m, ID 0.25
mm, oven temperature: 85°C; methyl 3-N-acetylamino
butanoate: Chiraldex b-PM 50 m×0.25 mm (astec),
130°C. The enantiomeric purity of 8 and its enantiomer
was determined using HPLC on a chiral stationary
phase (Chiralpack AD; eluent hexane:iso-PrOH=9:1).
All reagents were obtained from Aldrich and Merck.
Solvents were dried and freshly distilled under argon
before use. Reactions using phosphines and
organometallic compounds were performed under an

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I. V. Komaro6 et al. / Tetrahedron: Asymmetry 13 (2002) 1615–1620
4.2. (1R,7R)-7-(Bromomethyl)-1,7-dimethylbicyclo-
with sat. NaHCO3, 10% aqu. Na2SO3, again with sat.
NaHCO3 and finally with water (2×50 mL). The ether
solution was dried (Na2SO4) and evaporated. The iso-
meric lactones (2:1 ratio of 7 to its regioisomer accord-
ing to the 1H NMR of the crude mixture) were
separated by a flash chromatography (eluent: CHCl3),
to give the desired product 7 (0.35 g, 33% yield, mp
132–133°C, [h]3D0=+7.4, c 9.85×10−3, MeOH), then its
[2.2.1]heptane-2,3-dione, 5
A solution of (+)-9-bromocamphor7 (20 g, 86.5 mmol)
and SeO2 (freshly sublimed, 20 g, 180.2 mmol; toxic—
all operations were carried out in a good fumecup-
board) in AcOH (150 mL) was heated under reflux
under stirring for 12 h (the reaction was followed by
TLC, EtOAc–benzene, 8:1, Rf=0.76). After cooling to
room temperature, the mixture was filtered through
Celite. The Celite pad was washed with methanol. The
volatile products were removed on a rotary evaporator
(fumehood!). The residue was mixed with Et2O (200
mL), washed with water (2×50 mL), saturated NaHCO3
solution (100 mL), water (2×50 mL), and dried over
Na2SO4. Diethyl ether was distilled off and the product
was recrystallized from heptane. Yellow crystals (19.69
g, 80.3 mmol, 93% yield), mp 123–124°C (subl.). [h]3D0=
+77.5 (c 0.0213, MeOH). Anal. calcd for C10H13BrO2:
C, 49.00; H, 5.35. Found: C, 49.29; H, 5.37%. 1H NMR
(400.13 MHz, CDCl3) l: 3.62 (dd, J=10.7 and 0.8 Hz,
1H), 3.30 (d, J=10.7 Hz, 1H), (7-CH2Br); 3.01 (d,
J=5.2 Hz, 1H) (4-H); 2.10–2.20 (m, 1H), 1.90–2.00 (m,
1H), 1.65–1.75 (m, 2H), (5-CH2, 6-CH2); 1.17 (s, 3H),
(1-CH3); 1.10 (d, J=0.8 Hz, 3H), (7-CH3). 13C NMR
(100.63 MHz, CDCl3) l: 203.30 (CꢁO), 201.61 (CꢁO),
59.73 (C), 56.40 (CH), 47.49 (C), 35.90 (CH2), 29.25
(CH2), 22.26 (CH2), 18.16 (CH3), 9.58 (CH3).
1
isomer. H NMR (400.13 MHz, CDCl3) l: 4.41 (ddd,
J=11.1, 3.2 and 1.4 Hz, 1H) (4-Hexo); 4.15 (d, J=11.1
Hz, 1H) (4-Hendo); 3.39 (dq, J=10.3 and 1.2 Hz, 1H),
3.25 (d, J=10.3 Hz, 1H) (CH2Br); 2.46 (dd, J=6.7 and
3.2 Hz, 1H) (5-H); 2.08 (m 2H) (6-CH2); 1.95 (m, 2H)
(7-CH2); 1.18 (d, J=1.2 Hz, 3H) (8-CH3); 1.16 (s, 3H)
(1-CH3). 13C NMR (100.63 MHz, CDCl3) l: 175.9
(CꢁO), 74.4 (CH2O), 54.0 (C), 47.0 (C), 41.2 (CH), 40.4
(CH2), 35.9 (CH2), 26.7 (CH2), 17.1 (CH3), 14.4 (CH3).
4.5. (1R,2R,3S)-(2-Bromomethyl-3-hydroxymethyl-2,3-
dimethylcyclopentyl)methanol, 8
Method A. Lithium aluminium hydride (3 g, 79 mmol)
was cautiously added in small portions to a suspension
of
(1R,8R)-8-(bromomethyl)-1,8-dimethyl-3-oxabicy-
clo[3.2.1]octane-2,4-dione 6 (5 g, 19.1 mmol) in diethyl
ether (200 ml) under stirring. The mixture was heated
under reflux for 1 h, diluted with THF (150 ml) and
cooled in an ice bath. Under vigorous stirring and
cooling, water was carefully added to quench the excess
lithium aluminium hydride. The white precipitate of
hydroxides was filtered off and washed on the filter
several times with THF. The filtrate was evaporated,
dissolved in a CH2Cl2–MeOH (9:1) mixture, and
filtered through a small column packed with SiO2
(approx. 100 g). The eluate containing the product
(Rf=0.41) was collected, evaporated, and used for the
next step. An analytical sample was prepared by crys-
tallization from CHCl3. White crystals (3.72 g, 14.8
mmol, 78% yield), mp 116–117°C, [h]3D0=+33.4 (c 1.0,
MeOH). The enantiomeric purity was confirmed by
HPLC, where the opposite enantiomer was not
detected. The enantiomer was prepared starting from
(S)-camphor. Also in this case the other enantiomer
was not detected.
4.3. (1R,8R)-8-(Bromomethyl)-1,8-dimethyl-3-oxabicy-
clo[3.2.1]octane-2,4-dione, 6
Hydrogen peroxide (30% solution in water, 50 mL)
was added to a yellow solution of (1R,7R)-7-(bromo-
methyl) - 1,7 - dimethylbicyclo[2.2.1]heptane - 2,3 - dione
5 (10 g, 40.8 mmol) in AcOH (250 mL) under stirring.
The mixture was stirred at room temperature till it
became colourless (approx. 3.6 h). Then it was poured
into water (1 L). The white solid product was collected
by filtration, washed with water and air-dried. It was
sufficiently pure to be used directly in the next step. An
analytical sample was prepared by recrystallization
from diethyl ether. White crystals (9.75 g, 37.3 mmol,
92% yield), mp 152–153°C (subl.). [h]3D0=+365 (c 7.25×
10−3, MeOH). Anal. calcd for C10H13BrO3: C, 46.00; H,
5.02. Found: C, 46.16; H, 5.03%. 1H NMR (400.13
MHz, CDCl3) l: 3.37 (d, J=8 Hz, 1H), (5-H); 3.31
(ABq, J=10.7 Hz, 2H), (8-CH2Br); 2.10–2.25 (m, 2H),
1.95–2.05 (m, 2H), (6-CH2, 7-CH2); 1.28 (s, 3H), (CH3);
1.19 (s, 3H), (CH3). 13C NMR (100.63 MHz, CDCl3) l:
171.7 (CꢁO), 169.3 (CꢁO), 53.9 (C), 51.7 (CH), 47.8
(C), 36.9 (CH2), 33.4 (CH2), 24.3 (CH2), 17.3 (CH3),
14.3 (CH3).
Method B. The bromolactone 7 (150 mg, 0.61 mmol)
was dissolved in ether (10 mL), and LiAlH4 was added
cautiously (46.1 mg, 1.22 mmol) under stirring. The
mixture was stirred for 15 min. at ambient temperature.
The excess lithium aluminium hydride was quenched
with water, the precipitate filtered off and washed sev-
eral times with ether. The filtrate and washings com-
bined were dried (Na2SO4) and evaporated. The
product (153.2 mg, 100% yield) was sufficiently pure to
be used in the next step. Anal. calcd for C10H19BrO2: C,
47.82; H, 7.62. Found: C, 47.56; H, 7.40. 1H NMR
(400.13 MHz, CD3OD) l: 3.48–3.65 (m, 4H), 3.22–3.33
(m, 4H), (CH2O, CH2O, CH2Br); 2.08 (m, 1H), (1-H);
1.75–1.86 (m, 1H), 1.60–1.70 (m, 1H), 1.26–1.38 (m,
2H), (4-CH2, 5-CH2); 0.97 (s, 3H), (CH3); 0.88 (s, 3H),
(CH3). 13C NMR (100.63 MHz, CD3OD) l: 69.31
(CH2OH), 65.30 (CH2OH), 52.4 (C), 51.10 (CH), 49.5
(C, overlapped with the solvent residue signal), 45.50
4.4. (1R,5R,8R)-8-(Bromomethyl)-1,8-dimethyl-3-oxabi-
cyclo[3.2.1]octan-2-one, 7
A solution of (+)-9-bromocamphor (1 g, 4.3 mmol),
m-chloroperbenzoic acid (MCPBA) (1.12 g, 6.5 mmol)
and p-toluenesulfonic acid (0.1 g) in CH2Cl2 (40 mL)
was heated under reflux for 4 days. Each day an
additional portion of MCPBA (ꢀ40 mg) was added.
The mixture was diluted with ether (100 mL), washed

I. V. Komaro6 et al. / Tetrahedron: Asymmetry 13 (2002) 1615–1620
1619
(CH2Br), 36.15 (CH2), 27.35 (CH2), 20.39 (CH3), 16.36
(CH3).
4.8. [(1S,2S,3R)-1,2-Dimethyl-2,3-bis(diphenylphosphi-
nomethyl)cyclopentyl]methanol, 12
A solution of Ph2PLi (prepared from Ph2PCl (0.41 mL,
2.3 mmol) and Li (65 mg, 9.4 mmol) in 10 mL THF,
stirring at room temperature, 1 h, reflux, 2 h) was
added within 1 h to a solution of the O-protected
tosylate 10 (0.46 g, 0.94 mmol) in THF (5 mL) at 0–5°C
(ice bath) under stirring. The reaction mixture was
stirred first at room temperature for 2 h, and then
heated under reflux for 1.5 h. Water (20 mL) was
added, and the product was extracted with diethyl ether
(70 mL). The ether solution was washed twice with
water, evaporated and dried in high vacuum at 50°C
for 4 h. The residue was dissolved in ethanol (8 mL)
and pyridinium p-toluenesulfonate (25 mg) was added.
The solution was stirred at 55°C (bath temperature) for
2 days (TLC control, hexane–EtOAc, 1:1). The ethanol
was removed in vacuum, and the residue (dissolved in
acetone) was subjected to a flash chromatography. The
product 12 was eluted with pentane–Et2O (1:1), Rf=
4.6. [(1R,2R,3S)-2-(Bromomethyl)-3-(hydroxymethyl)-
2,3-dimethylcyclopentyl]methyl-4-methylbenzene sulfo-
nate, 9
4-Methylbenzenesulfonyl chloride (2.05 g, 10.7 mmol)
was added within 15 min to a solution of (1R,2R,3S)-
(2-bromomethyl-3-hydroxymethyl-2,3-dimethylcyclo-
pentyl)methanol 8 (2.7 g, 10.7 mmol) in dry pyridine
(10 mL) at −10°C under stirring. Then the mixture was
stirred at −10°C for 45 min. Water (70 mL) was added,
and the product was extracted with diethyl ether (150
ml). The ether layer was washed with water (50 ml), 5%
HCl (50 mL), water (3×50 mL), and dried over Na2SO4.
The solvent was evaporated (not raising the bath tem-
perature higher than 40°C), and the residue was
purified by column chromatography (eluent: CH2Cl2–
MeOH, 18:1). The ditosylate and the cyclic ether 11
were eluted first, following by the desired product 9
(Rf=0.5). The latter being a colourless oil (2.96 g, 7.3
mmol, 69% yield) was immediately used for the next
step. The non-converted diol 8 could finally be eluted
by CH2Cl2–MeOH (9:1) (0.8 g). The yield of the
product 9, calculated taking into account the recovered
starting diol was 97.2%. 1H NMR (400.13 MHz,
CDCl3) l: 7.77 (d, J=8.4 Hz, 2H); 7.34 (d, J=8.4 Hz,
2H); 4.30 (d, J=9.4 Hz, 1H); 4.01 (d, J=9.4 Hz, 1H);
3.75 (dd, J=10.6 and 7.1 Hz, 1H); 3.67 (d, J=10.6 Hz,
1H); 3.58 (dd, J=10.6 and 7.1 Hz, 1H); 3.54 (d, J=
10.6 Hz, 1H); 2.44 (s, 3H); 2.15 (m, 1H); 1.85 (m, 2H);
1.62 (m, 1H); 1.48 (m, 1H); 1.29 (m, 1H); 1.00 (s, 3H);
0.93 (s, 3H). 13C NMR (100.63 MHz, CDCl3) l: 145.20
(C), 133.23 (C), 130.27 (CH), 128.35 (CH), 76.52
(CH2O), 64.19 (CH2O), 49.42 (CH, C), 48.97 (C), 43.16
(CH2), 34.92 (CH2), 25.40 (CH2), 22.11 (CH3), 19.86
(CH3), 15.95 (CH3).
1
0.4. Viscous oil (210 mg, 43% yield). H NMR (400.13
MHz, C6D6) l: 7.75 (t, J=5.1 Hz, 2H), 7.58–7.62 (m,
4H), 7.57 (t, J=5.1 Hz, 2H), 6.95–7.10 (m, 12H),
(arom. protons); 3.75 (d, J=10.9 Hz, 1H), 3.30 (d,
J=10.9 Hz, 1H), (CH2O); 3.48 (br. s, 1H), (OH); 3.12
(dq, J=13 and 3 Hz, 1H), 1.9–2.0 (m, 1H), (2-CH2P);
2.63 (dd, J=14.9 and 3.4 Hz, 1H), 2.32 (dd, J=14.9
and 3.4 Hz, 1H), (3-CH2P); 2.19–2.30 (m, 2H), (4-CH2
6 ,
3-CH); 1.15–1.50 (m, 3H), (4-CH2, 5-CH2); 1.02 (s, 3H),
6
(1-CH3); 0.92 (s, 3H), (2-CH3). 13C NMR (100.63 MHz,
C6D6) l: 140–142, 133–134, 127–129 (m, arom.), 69.27
(s, O-CH2), 50.33 (s, 1-C), 49.08 (t, J=7.62 Hz, 2-C),
47.86 (dd, J=13.4 and 4.8 Hz, 3-CH), 37.37 (d, J=16.2
Hz, P-CH2), 34.92 (s, 5-CH2), 31.85 (dd, J=14.3 and
9.5 Hz, P-CH2), 29.48 (d, J=8.6 Hz, 4-CH2), 21.42 (s,
1-CH3), 17.80 (d, J=13.4 Hz, 2-CH3. 31P NMR (161.98
MHz, C6D6), l: −15.7, −22.7.
4.9. Preparation of [Rh(COD)(12)]BF4
To a stirred solution of the diphosphine 12 (1 mmol) in
THF (2 mL) [Rh(COD)(acac)] (311 mg, 1 mmol) was
added. The solution was stirred for 15 min. Then a
stoichiometric amount of aq. 40% HBF4 was added,
and stirring continued for another 15 min. The complex
was precipitated by ether (20 mL), dissolved in CH2Cl2
(0.5 mL), and precipitated by ether again. Dried in
vacuum for 5 h at 50°C. Yellow powder, contained
4.7. [(1R,2R,3S)-2-(Bromomethyl)-2,3-(dimethyl)-
3[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-
methyl-4-methylbenzenesulfonate, 10
Compound 9 (2.96 g, 7.3 mmol) was dissolved in
CH2Cl2 (20 mL). 3,4-Dihydro-2H-pyran (1 mL, 10.95
mmol) and pyridinium p-toluenesulfonate (PPTS) were
added. The mixture was stirred overnight at room
temperature. Diethyl ether (100 ml) was added and the
solution was washed with brine (50 mL) and water (50
mL). Then it was dried over Na2SO4, evaporated and
dried in high vacuum at 40°C for 2 h. The viscous oil
(3.57 g, 100% yield) was used in the next step without
1
nonstoichiometric amount of THF and ether. H NMR
(400.13 MHz, CDCl3) l: 8.05–8.20 (m, 4H), 7.1–7.8 (m,
16H), 4.30–4.48 (br. m, 3H), 4.06 (br. m, 1H), 3.72 (t,
J=3.8 Hz, 1H), 3.41 (d, J=11 Hz, 1H), 3.22 (m, 1H),
3.17 (d, J=11 Hz, 1H), 2.77 (dd, J=10 and 16 Hz,
1H), 1.95–2.45 (m, 9H), 1.55 (m, 2H), 1.35–1.5 (m, 4H),
0.79 (s, 3H), 0.48 (s, 3H). 13C NMR (100.63 MHz,
CDCl3) l: 125–135 (arom), 106.6, 102.1, 99.5, 96.6
(ꢁCH); 69.3 (OCH2), 51.4 (d, J=10.5 Hz, C), 47.6 (C),
44.7 (CH), 41.9 (d, J=17 Hz, P-CH2), 34.2 (d, J=17
Hz, P-CH2), 33.9 (CH2), 31.6 (CH2), 31.5 (CH2), 30.7
(CH2), 30.3 (CH2), 30.2 (CH2), 21.8 (CH3), 17.7 (CH3).
31P NMR (161.98 MHz, CDCl3), l: 22.3 (dd, J=41.6
and 144.3 Hz), 16.7 (dd, J=41.6 and 144.3 Hz). IR
(KBr, cm−1): 3550 [w(OH)].
1
further purification. H NMR (400.13 MHz, CDCl3) l:
7.76 (two d, 2H); 7.33 (d, J=8.5 Hz, 2H); 4.5 (m, 2H);
4.28 (dd, 1H); 3.0–4.0 (m, 6H); 2.44 (s, 3H); 1.1–2.4 (m,
11H); 0.85–1.05 (m, 6H). 13C NMR (100.63 MHz,
CDCl3) l: 145.1/144.3, 136.1, 133.5, 130.3, 129.5, 128.4,
100.1/99.1, 73.9/73.3, 68.6/67.4, 62.9/63.3, 59.1, 50.1,
48.4, 47.1/46.6, 35.09, 31.0, 26.5, 25.8, 22.1, 20.7, 20.1,
19.7, 16.5

1620
I. V. Komaro6 et al. / Tetrahedron: Asymmetry 13 (2002) 1615–1620
5. Money, T. Nat. Prod. Rep. 1985, 2, 253–289.
Acknowledgements
6. Komarov, I. V.; Gorichko, M. V.; Kornilov, M. Y.
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7. Lawrence, D. Ph.D. Thesis, UCLA, 1982.
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615.
The authors are grateful for a grant given by the
Alexander von Humboldt Foundation to I.K. We are
indebted to Degussa AG (Frankfurt) and the Fonds der
Chemischen Industrie for financial support. It is a
pleasure for us to acknowledge skilled technical assis-
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9. Toth, I.; Hanson, B. E. Organometallics 1993, 12, 1506–
1513.
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